Use of n-acetyl-d-aminoglycosamine in treatment of organ lesions related to toxicosis of drugs or chemicals

ABSTRACT

The present invention discloses a use of N-acetyl-D-glucosamine in the manufacture of a medicament for treating organ lesions caused by toxicants and drugs. A preparation comprising N-acetyl-D-glucosamine as main active component for treating organ lesions caused by toxicants and drugs exhibits merits of a directive action mechanism, significant therapeutical effects and simple manufacture and has no side effect.

TECHNICAL FIELD

The present invention relates to the use of N-acetyl-D-glucosamine orpharmaceutically acceptable salts thereof for in treating organ lesionscaused by toxicosis of drugs or toxicants, and the use ofN-acetyl-D-glucosamine or pharmaceutically acceptable salts thereof inthe manufacture of a medicament for treating organ lesions caused bytoxicosis of drugs or toxicants.

BACKGROUND ART

Many researches are directed to organ lesions caused by varioustoxicants and drugs. In daily life, various toxicants mainly enter intohuman body via respiratory tract, skin and digestive tract, and resultin multi-system and organ lesions. There are many injury mechanisms. Inlead poisoning, lead as a poly-affinity toxicant acts on all systems ofbody, and mainly injures nerve system, hematopoietic system, digestivesystem and cardiovascular system, wherein the most important injury isthe metabolism disorder of porphyrin, an intermediate product during thesynthesis of hemoglobin. In mercury poisoning, mercury ion binds tomercapto groups of enzymes in vivo, and thus inhibits the activity ofenzymes and blocks the normal metabolism of cells, which further causecentral nerve and autonomic nerve dysfunctions of central nerve andautonomic nerve and lesions of digestive tract and kidney. In poisoningof arsenic and compounds thereof, arsenic and oxides thereof bind tomercapto groups of cellular enzymes in vivo, in particular, they bind tothe mercapto group of pyruvate oxidase and inactivate this enzyme, whichaffect normal metabolism of cells and firstly result in lesions of nervesystem and blood capillary, so that human body exhibits toxic symptoms.In methanol poisoning, methanol mainly acts on central nerve system andbrings about a selective toxic effect, and the toxic symptoms aresimilar to alcoholism but more serious. Methanol destroys intracellularoxidization, so that the accumulation of lactic acid and other organicacids causes acid poisoning. Cyanide poisoning causes oxidizationdisorder in body, which results in so-called “intracellular choke”.Although there are various toxicosis mechanisms, most of them relate toeffects of cellular level on redox reactions during the metabolismprocess, or effects that toxicants act directly as oxidants, or effectsthat toxicants destroy activity of enzymes.

In drug poisoning, barbiturate poisoning mainly results in theinhibition of central nerve system, the most prominent toxic effect ofchloropromazine is extrapyramidal motor system dysfunction whichexhibits muscle convulsion, akathisia, etc. These symptoms cannot behealed for a long time after drug withdrawal.

At present, therapeutics for treating toxicosis of drugs and toxicantsinclude: intravenous injection of 10% calcium gluconate, 1-2 times perday, for 2-3 days, deleading therapy with sodium dimercaptosuccinate,de-arsenicing therapy with dimercaptopropanol, or gastrolavage;gastrolavage with sodium hydrogen carbonate or peritoneal dialysis fortreating methanol poisoning; therapy for treating cyanide poisoning byusing sodium thiosulfate, or glucose, or dicobalt edetate in combinationwith glucose. In general, said therapeutics are at the level ofcompetitive binding, quick dilution, concentration decrease and damagereduction, and there is essentially not therapeutics that has saidfunctions and can act against toxicants and drugs at sites of toxicaction in order to eliminate the toxic effect fundamentally.

N-acetyl-D-glucosamine is a chemical reagent. From the 1990's, it iscontinually used to treat diseases such as pericementitis (WO9102530A1),microbiological infection (WO9718790A3), intestinal inflammation(WO9953929A1), cornea disease (JP10287570A2), hypertrophy of theprostate (U.S. Pat. No. 5,116,615), and so on. It is also applied incosmetology (JP59013708A2), shampoo preparation (JP2011505A2), and thelike, but it has not been used in the manufacture of a medicament fortreating organ lesions caused by toxicosis of drugs or toxicants.

The inventor of the present invention finds that N-acetyl-D-glucosamineand pharmaceutically acceptable salts can rapidly and effectively treattoxic reactions of drugs and toxicants, competitively bind to toxicantsto convert toxicants into nontoxic substances, reduce oxidation-typetoxicants to alleviate their toxic effects on cell components, and forma dynamically changed isogeneric action barrier on surface of cells andbio-macromolecules to eliminate and segregate toxic effects, thereby thepresent invention is carried out.

CONTENTS OF THE INVENTION

One object of the present invention is to provide a use ofN-acetyl-D-glucosamine or pharmaceutically acceptable salts thereof inthe treatment of organ lesions caused by toxicosis of drugs ortoxicants.

Another object of the present invention is to provide a use ofN-acetyl-D-glucosamine or pharmaceutically acceptable salts thereof inthe manufacture of a medicament for the treatment of organ lesionscaused by toxicosis of drugs or toxicants.

Another object of the present invention is to provide a method fortreating organ lesions caused by toxicosis of drugs or toxicants,comprising administering a patient a pharmaceutical compositioncomprising an effective amount of N-acetyl-D-glucosamine orpharmaceutically acceptable salts thereof.

The said N-acetyl-D-glucosamine is a compound having a molecular formulaof C₈H₁₅NO₆ and a structure formula (I).

The examples of pharmaceutical acceptable salts ofN-acetyl-D-glucosamine that can be used in the present inventioninclude, but are not limited to the salts formed with inorganic acids,such as hydrochloride, hydrobromide, borate, phosphate, sulfate,hydrosulfate and hydrophosphate, and the salts formed with organicacids, such as citrate, benzoate, ascorbate, methylsulfate, picrate,fumarate, maleate, malonate, succinate, tartrate, mesylate, andglucose-1-phosphate.

In the pharmaceutical composition of the present invention, the contentof N-acetyl-D-glucosamine or pharmaceutically acceptable salts thereofis generally from 0.1 to 10% by weight.

Besides N-acetyl-D-glucosamine or pharmaceutically acceptable saltsthereof, the pharmaceutical composition of the present invention mayfurther comprise excipients or carriers well known in the art. Accordingto the desired administration manner, the person skilled in the art canreadily select suitable excipients or carriers.

The pharmaceutical composition of the present invention can be invarious dose forms and can be administrated in various manners, forexample, intestinal administration such as oral administration, orparenteral administration such as intravenous injection, transdermalinjection, etc. Typically, the pharmaceutical composition of the presentinvention is an injectable dose form, and is administered parenterally.For example, N-acetyl-D-glucosamine or pharmaceutically acceptable saltsthereof can be readily dissolved in injectable water or physiologicalsaline to form an injectable dose form.

The pharmaceutical composition of the present invention can beadministered in a manner of single dose per day or multidoses per day,such as 3-4 doses per day. The dose of said pharmaceutical compositiondepends on patient's age, condition, symptom, and administration manner.In general, as to an adult patient having a bodyweight of 75 kg, thedose of said pharmaceutical composition is 1-100000 mg per day,preferably 10-10000 mg per day, based on active component.

Another object of the present invention is to provide a process formanufacturing a pharmaceutical composition for treating organ lesionscaused by toxicosis of drugs and toxicants, comprising mixing antherapeutically effective amount of N-acetyl-D-glucosamine orpharmaceutically acceptable salts thereof with excipients or carriers toform a preparation.

Although the inventor does not intend to be restricted by any theory,the inventive point of the present invention is derived from the basicthinking of bio-wave theory. In the research of “bio-wave” theory, thepresent inventor has set up an organism wave-growth model. Throughdeeply researching the molecular mechanism of the organism wave-growth,the inventor puts forward a micro-heterology variation mechanism,wherein the change rate of biological wave of organism depends on thechange extent of outer environments. After the organism is wounded, theinner environments of said organism changes quickly, which promotes thegeneration of micro-heterology and disbalance between said organism andenvironments, and causes local lesions or systematic toxic symptoms.According to molecular biological analysis, these lesions and toxicsymptoms relate to the unstability even loss of function of proteins,especially various enzymes under changed conditions, especially changedtemperature in the presence of microorganism metabolism products.

The inventor confirms with experiments that N-acetyl-D-glucosamine orpharmaceutically acceptable salts thereof not only make organism cellsto reveal a normal bio-wave characteristic, but also cause the wavereveal a finer wave mode. This indicates that these compounds have afunction of promoting bio-waves. This wave-promoting function mayexplain the mechanism of treatment organ lesions caused by toxicants anddrugs.

The inventor finds that the supporting effect of N-acetyl-D-glucosamineand the antitoxic ability of binding to oxidation-type toxicants aresubstantively identical to that of glucose, while N-acetyl-D-glucosamineas a chiral drug has a diphase variation characteristics, which means itcan randomly bind to components of organism in an isologous manner oftoxic configuration of toxicants to form a segregation area between saidtoxicants and organism components such as cells or enzymes. As comparedto toxicants, N-acetyl-D-glucosamine has a higher affinity to organismcomponents, because N-acetyl-D-glucosamine has a dynamically changeableconfiguration that can randomly maintain changeable featurescorresponding to configurations of biomacromolecules. This ability isimportant in natural protection mechanism of stabilizing structure andfunction of cells or molecules thereof formed via natural evolution ofendogenous substances that are present in vivo for a long-term.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

The beneficial effects of the present invention are further demonstratedby the following examples, but it shall be understood that theseexamples are merely to illustrate the present invention, rather than torestrict the scope of the present invention in any aspect.

EXAMPLE 1 Promoting Wave Test of the Compound of Formula (I)

1. Experimental Materials and Method:

1.1 Sample: Pure Compound of Formula (I)

1.2 Experimental Materials:

-   -   Strain: Proteus Mirabilis that meets the following biochemical        reaction characteristics: dynamics (+), urease (+), lactose (−),        glucose (+), H₂S (−), phenylalanine deaminase (+).    -   Culture medium: modified LB culture medium (components: 1%        tryptones, 0.5% yeast extract, 1% sodium chloride, 0.1% glucose,        0.002% TTC, and pH=7.2 to 7.4).        1.3 Experimental Method:    -   Control sample: the Proteus Mirabilis were inoculated at the        center of LB plate, and incubated at 37° C. for 9 hours;    -   Test sample: the compound of formula (I) with a final        concentration of 0.5% was added to the LB plate, then the        Proteus Mirabilis were inoculated by the same method, and        cultured at 37° C. for 9 hours.        2. Experimental Results and Evaluation:    -   The control sample exhibited concentric rings with an interval        of 3 hours, which extended outward continually. The test sample        showed not only concentric rings with an interval of 3 hours,        but also many fine waves on each ring in comparison with the        control sample.    -   The experiment adopts a bio-wave model to research the promoting        wave function of the compound of formula (1). The results showed        that the compound of formula (I) was not only able to cause        bacterial cell to reveal a normal bio-wave characteristic, but        also cause the wave reveal finer wave mode. These indicated that        the compound of formula (I) has a function of promoting        bio-waves. It is anticipated that this wave-promoting function        could treat organ lesions caused by toxicants and drugs.

EXAMPLE 2 Toxicological Test of the Compound of Formula (I)

The toxicological test of the compound of formula (I) includes:

-   1. Acute toxicity test: including tests of oral administration,    intravenous injection administration, and maximum limit amount for    administration;-   2. Ames test;-   3. Micronucleus test of mouse bone marrow cell;-   4. Abnormality test of mouse sperm;-   5. Aberration test of mouse testis chromosome;-   6. Chronic lethal test;-   7. Sub-chronic toxicity (feed for 90 days) test;-   8. Traditional deformity-inducing test.

The results of these tests showed that in the acute toxicity test of thecompound of formula (I), the acute toxicosis reaction had not appearedwhen the dosage more than 2 g/kg was taken; in the long-period toxicitytest, the maximum dosage had reached up to 1 g/kg, and after thetreatment and observation for four weeks, there was no intoxicationreaction yet; and in the reproduction test, the mice were feed with aroutine dosage of 7 mg/kg for 3 generations, it had been proved that thecompound of formula (I) had no influence on the pregnancy, birth, nurse,and the growth of baby mice, so that the compound of formula (I) is asubstance without toxicity.

EXAMPLE 3 Animal Tests

1. Methanol Poisoning Test

30 Kunming mice were randomly divided into two groups, i.e., 15 mice intest group (I) and 15 mice in test group (II), and another 15 mice wereused as control. Each mouse was fed with methanol in a dose of 0.2 ml/20g bodyweight. The mice of the control group were not treated, whereinthe mice exhibited delirium, colliding things and blurred vision, 13mice were blind in both eyes and myasthenia of limbs within about 2hours, 10 mice sequentially died and 3 mice still were blind. The miceof the test group (I) were intra-peritoneally injected with an aqueoussolution of N-acetyl-D-glucosamine having a concentration of 0.1 g/ml ina dose of 0.1 ml/20 g bodyweight, just after they were fed withmethanol. The results showed that 8 mice were blind after 2 hours(wherein 5 mice sequentially died), and 2 mice exhibited obviouspsychiatric symptoms. The mice of the test group (II) wereintra-peritoneally injected with an aqueous solution ofN-acetyl-D-glucosamine having a concentration of 0.1 g/ml in a dose of 2ml/20 g bodyweight, just after they were fed with methanol. The resultsshowed that the mice exhibited better condition, wherein 4 miceexhibited delirium and myasthenia of limbs, no mouse was blind, and 2mice died within 12 hours.

2. Rogor Poisoning Test

30 Kunming mice were randomly divided into three groups, i.e., 10 micein control group, 10 mice in test group (I) and 10 mice in test group(II). The mice were orally fed with 10000 times diluted rogor stocksolution (commercially obtained from Chongqing Agriculture ChemicalsGroup, 500 ml/bottle, standard: GB15583-1995) in a dose of 0.5 ml permouse for consecutive 3 days. The mice of the control group were nottreated, and exhibited toxic symptoms of food-intake reduction anddysphoria after they were continuously fed for 3 days, then exhibiteddiarrhoea, watery stool, blurred vision during action, some miceexhibited symptoms of coma, twitch, urinary and fecal incontinence,etc., and 8 mice died. The mice of the test groups were treated byintra-peritoneal injection of an aqueous solution ofN-acetyl-D-glucosamine having a concentration of 5 g/100 ml in a dose of0.2 ml for the test group (I) and a dose of 2 ml for the test group(II). The results showed that 4 mice died in the test group (I) and 1mouse died in the test group (II), and the corresponding symptoms werewell controlled. The mice of test groups were significantly differentfrom the mice of the control group.

3. Lead Poisoning Test

30 Kunming mice were made as lead poisoning models by a method offeeding litharge. The mice of control group, i.e., model group were nottreated, wherein the mice exhibited obvious symptoms of polysialia,emesis, diarrhoea, constipation, twitch, etc., the death rate was 8/10within 3 days, and the death rate was 10/10 within 7 days. The mice ofthe test group (I) were treated by intra-peritoneal injection ofN-acetyl-D-glucosamine in a dose of 0.2 ml×10% (weight/volume), and themice of the test group (II) were treated by intra-peritoneal injectionwith N-acetyl-D-glucosamine in a dose of 2 ml×10% (weight/volume). Thedeath rate of mice was separately 7/10 and 2/10 within 3 days, and thedeath rate of mice was 1/3 and 0/8 within the following 4 days. Thesurvival mice exhibited better conditions. N-acetyl-D-glucosamine showedobviously function of treating reaction of lead poisoning, controllingrelevant symptoms, and reducing death rate.

According to the above examples, N-acetyl-D-glucosamine can effectivelyeliminate toxic effects of at least toxicants such as metal ions,organophosphorus pesticides, methanol, etc. that have different actionmechanisms.

The compound of the formula (I) of the present invention not only hascertain effect, but also does not exhibit side-effect as conventionalantidotes. Hence, it is a promising drug.

1. A use of N-acetyl-D-glucosamine or pharmaceutically acceptable saltsthereof in the manufacture of a medicament for treating organ lesionscaused by toxicants and drugs.
 2. A use according to claim 1, whereinsaid medicament is of an injectable form and is parenterallyadministered.
 3. A use according to 1 or 2, wherein theN-acetyl-D-glucosamine or pharmaceutically acceptable salts thereof insaid medicament has a concentration of 0.1-10% by weight.
 4. A use ofN-acetyl-D-glucosamine or pharmaceutically acceptable salts thereof intreating organ lesions caused by toxicants and drugs.
 5. A method fortreating organ lesions caused by toxicants and drugs, comprisingadministering a patient a pharmaceutical composition comprising aneffective amount of N-acetyl-D-glucosamine or pharmaceuticallyacceptable salts thereof.
 6. A method according to claim 5, wherein saidpharmaceutical composition is of an injectable form and is parenterallyadministered.
 7. A use according to 5 or 6, wherein theN-acetyl-D-glucosamine or pharmaceutically acceptable salts thereof insaid pharmaceutical composition has a concentration of 0.1-10% byweight.